Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia

Tslil Ast, Hong Wang, Eizo Marutani, Fumiaki Nagashima, Rajeev Malhotra, Fumito Ichinose, Vamsi K Mootha, Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia, Human Molecular Genetics, 2023;, ddad091, doi:10.1093/hmg/ddad091 

 The detrimental effect of this regimen is likely due to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.